Doktor, T. K., Hua, Y., Andersen, H. S., Broner, S., Liu, Y. H., Wieckowska, A., Dembic, M., Bruun, G. H., Krainer, A. R., Andresen, B. S. (January 2017) RNA-sequencing of a mouse-model of spinal muscular atrophy reveals tissue-wide changes in splicing of U12-dependent introns. Nucleic Acids Res, 45 (1). pp. 395-416. ISSN 1362-4962 (Electronic)0305-1048 (Linking)
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Abstract
Spinal Muscular Atrophy (SMA) is a neuromuscular disorder caused by insufficient levels of the Survival of Motor Neuron (SMN) protein. SMN is expressed ubiquitously and functions in RNA processing pathways that include trafficking of mRNA and assembly of snRNP complexes. Importantly, SMA severity is correlated with decreased snRNP assembly activity. In particular, the minor spliceosomal snRNPs are affected, and some U12-dependent introns have been reported to be aberrantly spliced in patient cells and animal models. SMA is characterized by loss of motor neurons, but the underlying mechanism is largely unknown. It is likely that aberrant splicing of genes expressed in motor neurons is involved in SMA pathogenesis, but increasing evidence indicates that pathologies also exist in other tissues. We present here a comprehensive RNA-seq study that covers multiple tissues in an SMA mouse model. We show elevated U12-intron retention in all examined tissues from SMA mice, and that U12-dependent intron retention is induced upon siRNA knock-down of SMN in HeLa cells. Furthermore, we show that retention of U12-dependent introns is mitigated by ASO treatment of SMA mice and that many transcriptional changes are reversed. Finally, we report on missplicing of several Ca2+ channel genes that may explain disrupted Ca2+ homeostasis in SMA and activation of Cdk5.
| Item Type: | Paper |
|---|---|
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > introns > intron splicing Investigative techniques and equipment > assays > RNA-seq diseases & disorders > congenital hereditary genetic diseases > spinal muscular atrophy |
| CSHL Authors: | |
| Communities: | CSHL labs > Krainer lab |
| Depositing User: | Matt Covey |
| Date: | 9 January 2017 |
| Date Deposited: | 26 Aug 2016 21:26 |
| Last Modified: | 08 Nov 2017 15:07 |
| PMCID: | PMC5224493 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/33399 |
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